1. Juvenile methylphenidate modulates reward-related behaviors and cerebral blood flow by decreasing cortical D3 receptors.
- Author
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Andersen SL, Napierata L, Brenhouse HC, and Sonntag KC
- Subjects
- Age Factors, Aging physiology, Animals, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity metabolism, Attention Deficit Disorder with Hyperactivity physiopathology, Avoidance Learning drug effects, Avoidance Learning physiology, Behavior, Animal drug effects, Behavior, Animal physiology, Brain Chemistry drug effects, Brain Chemistry physiology, Cerebral Cortex blood supply, Cerebrovascular Circulation physiology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dopamine Uptake Inhibitors pharmacology, Drug Interactions physiology, Male, RNA, Messenger drug effects, RNA, Messenger metabolism, Rats, Receptors, Dopamine D3 genetics, Receptors, Dopamine D3 metabolism, Cerebral Cortex drug effects, Cerebral Cortex growth & development, Cerebrovascular Circulation drug effects, Dopamine metabolism, Methylphenidate pharmacology, Receptors, Dopamine D3 drug effects, Reward
- Abstract
Attention deficit hyperactivity disorder is associated with reduced cortical blood flow that is reversible with exposure to the psychostimulant methylphenidate (MPH). D3 dopamine receptors modulate stimulant-induced changes in blood flow and are associated with reward processing during young adulthood, but their role in the enduring effects of MPH during development is unknown. Rats were given vehicle (VEH) or MPH (2 mg/kg between postnatal days 20-35) and assessed in young adulthood for regional cerebral blood volume (rCBV) after MPH challenge and mRNA expression levels of dopamine receptors. To probe D3 receptor involvement, juvenile subjects were exposed to VEH, MPH, the D3-preferring agonist +/-7-OHDPAT (0.3 mg/kg), the D3 antagonist nafadotride (Naf; 0.05, 0.5 or 5.0 mg/kg) or a Naf (0.05 mg/kg)/MPH combination, and assessed biochemically and behaviorally. Juvenile MPH exposure increased MPH-induced rCBV in the cingulate and medial prefrontal cortex and thalamus in adulthood. Behaviorally, juvenile MPH- or +/-7-OHDPAT-exposed subjects demonstrated an aversion to cocaine-associated environments, which was prevented by juvenile co-treatment with MPH and Naf, or with adult cortical microinjections of +/-7-OHDPAT. Cortical D3 mRNA levels significantly decreased by 23.8 +/- 6.7% in MPH-treated subjects and normalized with combined Naf/MPH treatment, with no change in the other dopamine receptors. Enhanced cortical responsiveness to psychostimulants may occur through a reduction in D3 receptors, which in turn reduces drug-seeking behavior. These data provide evidence for a postnatal sensitive period when juvenile MPH exposure is able to alter cortical development.
- Published
- 2008
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